5-HTergic system pathology in late life major depression may distinguish patients with poor treatment outcome. Clinical studies have shown that the key distinguishing factor correlated with failure to achieve remission is late age of depression onset; the prototypical disorder of this type is VsD. In contrast, older patients with early onset recurrent major depression (EORD) have more favorable course following antidepressant treatment. Multiple lines of evidence have suggested that alterations in postsynaptic 5-HT receptors play a key role in pathophysiology. We hypothesize that 5-HT receptor-specific PET imaging will discriminate the effect of treatment on early-onset and VsD when compared with controls, and that this will demonstrate 5-HTergic abnormalities in subgroups of patients with late life depression. We propose a treatment study of patients with protypical treatment responsive and treatment refractory depression: EORD (n=18) and VsD (n=18), respectively, and controls (n=18 at baseline) using F-altanserin, a selective PET agent for imaging the 5-HT receptor: (1) to quantify 5-HT receptor binding and test for differences between patients with untreated EORD and VsD, and normal controls; (2) to quantify 5-HT receptors after treatment with an 5-HT reuptake inhibitor (SSRI) and test for differences between EORD and VsD and (3) to correlate changes in 5-HT receptor binding following SSRI treatment and clinical response to treatment. All subjects will be studied at baseline, and depressed subjects again after chronic treatment (8 weeks) with sertraline. Repeated measures ANOVA will be used to determine group differences. Pearson correlations will be used to correlate changes in 5-HT densities and clinical response (HAMD). We hypothesize: (1) that the 5-HT receptor density will be lower in medial prefrontal cortex and hippocampus in patients with both EORD and VsD than in controls will negatively correlate with baseline HAMD score; (2) that relative to patients with EORD, patients with VsD will have less change in 5-HT receptor binding in the medial prefrontal cortex and hippocampus following antidepressant treatment; and (3) that the magnitude of downregulation of 5-HT receptors in medial prefrontal cortex and hippocampus after SSRI treatment will correlate with the degree of treatment response. This information will lead to better understanding of the pathogenesis of late life depression and may contribute to improvements in antidepressants treatment design.